Summary: (at least 500 but no more the 7900 characters including spaces) At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeficiency virus (HIV) should be stopped in the setting of elevated liver enzymes. In large part, this is due to a limited understanding of the natural history of ARV-related hepatotoxicity. We have undertaken a pilot study (Caryn Morse is PI) to estimate the prevalence of hepatic fibrosis in a cohort of HIV-infected patients who have chronically elevated transaminases while on ARV therapy in the absence of Hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens are being evaluated for fibrosis by microscopic examination, the current gold standard for assessing the nature and severity of liver disease. Fibrosis, as well as other histopathology, is being measured using a validated scoring system. Sixty-two patients have enrolled in the study and undergone liver biopsy. Significant liver abnormalities, primarily steatohepatitis, but also fibrosis, have been seen in the 40 patients. A paper describing the histopathologic abnormalities and clinical correlates of these patients has been published. We plan to continue to follow these patients long-term to better understand the natural history of these liver abnormalities. We have also examined the predictive value of Fibroscans, which were performed in parallel with other evaluations, for identifying fibrosis in patients with elevated transaminases but without HBV or HCV co-infection. This study will provide clinically relevant information on the significance of elevated transaminases in HIV-infected patients without co-infection with HCV or HBV, and facilitate management of such patients. Biomarkers including D-dimer and IL-6 have been shown to predict mortality in HIV-infected patients, independent of CD4 and viral load. To better understand the mechanism leading to D-dimer elevation, we have undertaken a cross-sectional study to examine markers of coagulation, platelet function, endothelial activation and inflammation, and to identify correlates of elevated D-dimer levels. Our hope is that this analysis will provide insights into which of these pathways is leading to D-dimer elevation. To date we have enrolled approximately 230 HIV+ patients and HIV-volunteers. Preliminary analysis suggests that TNF-alpha, sVCAM, andvon Willebrand Factor correlate with levels of D-Dimer. These data suggest that ongoing monocyte activation plays a role in D-dimer elevation. We have enrolled an additional 60 patients to study the correlates of immunologic non-response in patients receiving HAART, including 30 subjects and 30 controls. We plan to examine immunophenotypic characteristics of the patients, as well as look for evidence of infection with a variety of viral pathogens, including unknown viruses. We are in the process of examining T-cell receptor repertoire diversity, as well as a detailed flow cytometry panel, biomarker panel, and RNA expression levels using microarrays. We are also planning to examine whole exome sequencing of a subset of these patients to see if there are any genetic markers that can distinguish immunologic non-responders from responders to HAART. The goal is to better understand the mechanisms leading to poor immunologic response in HIV-infected patients.